Prostate carcinogenesis involves transformation of zinc-accumulating normal epithelial cells to malignant cells, which do not accumulate zinc. We demonstrate that physiological levels of zinc inhibit activation of NFkappaB transcription factor, suppress expression of NF-kappaB-regulated proteins involved in angiogenesis and metastasis including VEGF, IL-8 and MMP-9 and sensitize prostate cancer cells to androgen deprivation and cytotoxic agents. Genes controlled by NF-kappaB contribute to malignant transformation, drug resistance and cancer progression to hormone-independent growth. The overall objective of the current proposal is to explore the role of zinc and zinc import and export proteins in the pathogenesis and progression of prostate malignancy and mechanisms of their regulation. We hypothesize that overexpression of zinc importers (hZIP1 and hZIP2) or reduced expression of proteins responsible for zinc export and intracellular distribution (ZnT1 through 9) has a functional impact on NF-kappaB activity, growth and viability of prostate cancer cells in vitro and in vivo. Specific Aim 1 will examine the expression and mechanisms of regulation of zinc import and export proteins in normal and transformed prostate cells. Specific Aim 2 will determine whether increased intracellular zinc accumulation via modulation of zinc import and export protein expression has a functional impact on NF-kappaB activity, growth and viability of prostate cancer cells. Specific Aim 3 will determine if overexpression of human zinc uptake transporters hZIP1 and hZIP2 inhibits prostate tumor progression in vivo. Parental prostate cancer cells or cells transfected with either hZIP1 or hZIP2 will be injected orthotopically into nude mice. The effects of dietary zinc supplementation on tumor growth will be examined. The proposed studies will help to understand the role of zinc in the pathogenesis of prostate malignancy and therefore, might have important consequences for the prevention and treatment of prostate cancer. [unreadable] [unreadable]